Cell penetrating peptides (CPP) are highly cationic, hydrophilic, short, peptides capable of translocating across the cell membrane. These peptides have the special property of carrying with them cargoes of a wide range of molecular size such as proteins, nucleic acids, peptide nucleic acids, and other biological and non biological molecules. These peptides have been widely studied as means of delivering macromolecules to cells for therapeutic purposes. It is anticipated that the further development and refinement of CPP techniques will provide drug delivery vectors, cellular imaging techniques, and molecular therapeutics. The objective of the proposed research is to develop an atomic level model of the mechanism and energy of translocation of these peptides across lipid bilayers. This model will provide the basis of further development of CPP sequences that effectively translocate across cell membranes. We will also study the effect secondary structure and sequence on the interaction of the CPP peptides with membranes. These studies will help us design new sequences that will translocate more efficiently, and will therefore require smaller dosage of CPPs. We also postulate that some cationic antimicrobial peptides (AMP), like protegin-1, will insert into the lipid bilayer by a mechanism that shares many features with the mechanism of translocation of cell penetrating peptides. We will study the interaction of PG-1 with model lipid bilayers that mimic bacterial and eukaryote cell membranes to understand the selectivity of AMP to bacterial cells. Our studies are based on extensive molecular dynamics simulations and molecular modeling. Our research may lead to the development of better cell penetrating peptides and new antimicrobial peptides. PUBLIC HEALTH RELEVANCE: Cell penetrating peptides have the special property of carrying with them cargos of a wide range of molecular size such as proteins, nucleic acids, peptide nucleic acids, and other biological and non biological molecules. These peptides have been widely studied as means of delivering macromolecules to cells for therapeutic purposes. This project aims at developing an atomic level description of the up to now elusive mechanism of translocation of these peptides across cells. The elucidation of this mechanism will enable the development of more efficient delivery vectors for imaging and therapeutic purposes.